Depressed HCN4 function in the type 2 diabetic sinoatrial node

Diabetic patients often have impaired heart rate (HR) control. HR is regulated both intrinsically within the sinoatrial node (SAN) and via neuronal input. Previously, we found lower ex vivo HR in type 2 diabetic rat hearts, suggesting impaired HR generation within the SAN. The major driver of pacema...

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Bibliographic Details
Published in:	Molecular and cellular biochemistry Vol. 478; no. 8; pp. 1825 - 1833
Main Authors:	Parveen, Sajida, Cheah, Paddy H. S., Worthington, Luke P. I., Smither, Roseanna A., Munro, Michelle L., Bussey, Carol T., Lamberts, Regis R., Jones, Peter P.
Format:	Journal Article
Language:	English
Published:	New York Springer US 01-08-2023 Springer Springer Nature B.V
Subjects:	Animals Aprotinin Biochemistry Biomedical and Life Sciences Cancer Research Cardiology Cardiomyocytes Diabetes Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 - metabolism Ethylenediaminetetraacetic acid Heart beat Heart rate Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - metabolism Immunofluorescence Ion channels (cyclic nucleotide-gated) Ivabradine Life Sciences Medical Biochemistry Membrane proteins Membranes Myocytes, Cardiac - metabolism Nucleotides Potassium Channels - metabolism Protein expression Proteins Rats Rats, Zucker Sinoatrial Node - metabolism Type 2 diabetes Type 2 diabetes Heart rate Sinoatrial node
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Summary:	Diabetic patients often have impaired heart rate (HR) control. HR is regulated both intrinsically within the sinoatrial node (SAN) and via neuronal input. Previously, we found lower ex vivo HR in type 2 diabetic rat hearts, suggesting impaired HR generation within the SAN. The major driver of pacemaking within the SAN is the activity of hyperpolarisation-activated cyclic nucleotide-gated 4 (HCN(4)) channels. This study aimed to investigate whether the lower intrinsic HR in the type 2 diabetic heart is due to changes in HCN4 function, protein expression and/ or distribution. The intrinsic HR response to HCN4 blockade was determined in isolated Langendorff-perfused hearts of Zucker type 2 Diabetic Fatty (ZDF) rats (DM) and their non-diabetic ZDF littermates (nDM). HCN4 protein expression and membrane localisation were determined using western blot and immunofluorescence, respectively. We found that the intrinsic HR was lower in DM compared to nDM hearts. The change in intrinsic HR in response to HCN4 blockade with ivabradine was diminished in DM hearts, which normalised the intrinsic HR between the groups. HCN4 protein expression was decreased in the SAN of DM compared to nDM controls with no change in the fraction of HCN4 localised to the membrane of SAN cardiomyocytes. The lower intrinsic HR in DM is likely due to decreased HCN4 expression and depressed HCN4 function. Our study provides a novel understanding into the intrinsic mechanisms underlying altered HR control in type 2 diabetes.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0300-8177 1573-4919
DOI:	10.1007/s11010-022-04635-6